It is proposed to prepare the anticancer alkaloid Pseudolycorine (and epipseudolycorine) via two basic approaches, namely intramolecular-gamma-alkylation of enaminoketones and the intramolecular alpha-alkylation of an aminoketone. Each of these methods provides for direct formation of the D-ring of these tetracyclic alkaloids and for creation of the required stereochemistry and functionality that gives this system vincristine-like-anticancer chemotherapeutic properties. It is proposed to synthesize the cytotoxic sesquiterpene lactone system encelin, a naturally occurring alpha-methylene-gamma-butyrolactone, and "hydroxy" and "alkoxy"-encelin, the latter systems of which have not been found in nature. The synthetic approaches to this system entail two general considerations, the first of which utilizes vinylogous thioesters which we have previously converted to beta-cyperone, one of the simplest members of this class of eudesman sesquiterpenes. A combination of alpha-alkylations, sulfur modifications and extended cross conjugated enolate alkylations (or oxidations) will be present a general synthon usable for not only encelin and hydroxyencelin synthesis, but also santonin, yomogin, arglamine, santamarine and many other important sesquiterpenes. Our second approach is designed to yield specifically encelin via Diels-Alder chemistry in four formal steps. The encelin system is one of the most active cytotoxic sesquiterpene systems yet isolated from plant sources. It is a major goal of this proposal to confirm the mode of action of this (encelin) and other sesquiterpene systems as sulfur (protein-sulfhydryl group) alkylating agents. Further, we are prepared to and will be testing all synthetic intermediates, as well as our final goal or target compounds against L1210 mouse leukemia in our department (Department of Chemistry, USC), before we seek additional testing through NCI's facilities.